65 research outputs found

    Microfluidic-integrated vertical electrodes employed in impedance-based cytometry:potential application in immunotherapies

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    During the last decades, the growing interest for single-cell analysis has led to the creation of a number of microfluidic and lab-on-a chip (LOC) platforms for characterizing cellular samples. In that context label-free based platforms are minimally invasive and offer the notable advantages of reducing alteration of the analyzed sample and granting its re-employment. The study of intrinsic features of single cells independent from markers is commonly attained using electrical and mechanical-based techniques. Electrical-based techniques have been widely employed in LOC applications, both for characterizing and for manipulating cell samples. The translation of these approaches to single-cells necessitates microelectrodes that can be singularly addressed and arranged in a high-density topography. This thesis provides two fabrication solutions that comply with these requirements and allow to manufacture highly conductive vertical platinum microelectrodes with high aspect-ratio. According to the two processes reported, the three-dimensional (3D) cores of the electrodes are fabricated in SU-8 or in silicon respectively. These tridimensional structures are successively coated by a metal layer, after a passivation step in the case of silicon. The planar metal connections which singularly address the free-standing microelectrodes are patterned differently for the two approaches, respectively by lift-off and spray coating. Importantly, the 3D microelectrodes can be co-fabricated with microfluidic structures to obtain multiple active sites for single-cell analysis. In this thesis, in the framework of a collaboration with Ludwig Centre for Cancer Biology (Lausanne, Switzerland), the microelectrodes have been employed to detect activated T cells. The encouraging results pave the way to a new generation of microfluidic platform based on 3D microelectrodes to attain real-time and label-free monitoring of individual T cells to employ in immunotherapy

    Microfluidics for Biosensing and Diagnostics

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    Efforts to miniaturize sensing and diagnostic devices and to integrate multiple functions into one device have caused massive growth in the field of microfluidics and this integration is now recognized as an important feature of most new diagnostic approaches. These approaches have and continue to change the field of biosensing and diagnostics. In this Special Issue, we present a small collection of works describing microfluidics with applications in biosensing and diagnostics

    COMPUTATIONAL ANALYSIS OF CODE-MULTIPLEXED COULTER SENSOR SIGNALS

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    Nowadays, lab-on-a-chip (LoC) technology has been applied in a variety of applications because of its capability to perform accurate microscale manipulations of cells for point-of-care diagnostics. On the other hand, such a result is not readily available from an LoC device and typically still requires a post-inspection of the chip using traditional laboratory equipment such as a microscope, negating the advantages of the LoC technology. To solve this dilemma, my doctoral research mainly focuses on developing portable and disposable biosensors for interfacing with and digitizing the information from an LoC system. Our sensor platform, integrated with multiple microfluidic impedance sensors, electrically monitors and tracks manipulated cells on an LoC device. The sensor platform compresses information from each sensor into a 1-dimensional electrical waveform, and therefore, further signal processing is required to recover the readout of each sensor and extract information of detected cells. Furthermore, with the capability of the sensor platform, we have introduced integrated microfluidic cytometers to characterize properties of cells such as cell surface expression and mechanical properties.Ph.D

    On-chip wireless silicon photonics: From reconfigurable interconnects to lab-on-chip devices

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    [EN] Photonic integrated circuits are developing as key enabling components for high-performance computing and advanced network-on-chip, as well as other emerging technologies such as lab-on-chip sensors, with relevant applications in areas from medicine and biotechnology to aerospace. These demanding applications will require novel features, such as dynamically reconfigurable light pathways, obtained by properly harnessing on-chip optical radiation. In this paper, we introduce a broadband, high-directivity (>150), low-loss, and reconfigurable silicon photonics nanoantenna that fully enables on-chip radiation control. We propose the use of these nanoantennas as versatile building blocks to develop wireless (unguided) silicon photonic devices, which considerably enhance the range of achievable integrated photonic functionalities. As examples of applications, we demonstrate 160 Gbit·s-1 data transmission over mm-scale wireless interconnects, a compact low-crosstalk 12-port crossing, and electrically reconfigurable pathways via optical beam steering. Moreover, the realization of a flow micro-cytometer for particle characterization demonstrates the smart system integration potential of our approach as lab-on-chip devices.Funding from grant TEC2015-63838-C3-1-R OPTONANOSENS (MINECO/FEDER, UE) is acknowledged. This work was also supported by project TEC2015-73581-JIN (AEI/FEDER, UE), the EU-funded projects FP7-ICT PHOXTROT (No.318240) and H2020-, the EU-funded H2020-FET-HPC EXANEST (No.671553) and the Generalitat Valenciana's PROMETEO grant NANOMET PLUS (PROMETEO II/2014/34) CG-M acknowledges support from Generalitat Valenciana’s VALi+d postdoctoral program (exp. APOSTD/ 2014/044). We thank David Zurita for his help in the design of the data acquisition code for the sensing application.García Meca, C.; Lechago-Buendia, S.; Brimont, ACJ.; Griol Barres, A.; Mas Gómez, SM.; Sánchez Diana, LD.; Bellieres, LC.... (2017). On-chip wireless silicon photonics: From reconfigurable interconnects to lab-on-chip devices. Light: Science & Applications. 6:e17053-e17053. https://doi.org/10.1038/lsa.2017.53e17053e170536Kirchain R, Kimerling R . A roadmap for nanophotonics. Nat Photonics 2007; 1: 303–305.Fan XD, White IM . Optofluidic microsystems for chemical and biological analysis. Nat Photonics 2011; 5: 591–597.Zhuang LM, Roeloffzen CGH, Meijerink A, Burla M, Marpaung DAI et al. Novel ring resonator-based integrated photonic beamformer for broadband phased array receive antennas—part II: experimental prototype. J Lightw Technol 2010; 28: 19–31.Yu NF, Capasso F . Flat optics with designer metasurfaces. Nat Mater 2014; 13: 139–150.Condrat C, Kalla P, Blair S . Crossing-aware channel routing for integrated optics. IEEE Trans Comput-Aided Design Integr Circuits Syst 2014; 33: 814–825.Lee BG, Rylyakov AV, Green WMJ, Assefa S, Baks CW et al. Monolithic silicon integration of scaled photonic switch fabrics, CMOS logic, and device driver circuits. J Lightw Technol 2014; 32: 743–751.Robinson JP, Roederer M . Flow cytometry strikes gold. Science 2015; 350: 739–740.Mao XL, Nawaz AA, Lin SC, Lapsley MI, Zhao YH et al. An integrated, multiparametric flow cytometry chip using 'microfluidic drifting' based three-dimensional hydrodynamic focusing. Biomicrofluidics 2012; 6: 024113.Schurr JM . Dynamic light scattering of biopolymers and biocolloids. CRC Crit Rev Biochem 1977; 4: 371–431.Padgett M, Bowman R . Tweezers with a twist. Nat Photonics 2011; 5: 343–348.Haurylau M, Chen GQ, Chen H, Zhang JD, Nelson NA et al. On-chip optical interconnect roadmap: challenges and critical directions. IEEE J Select Top Quantum Electron 2006; 12: 1699–1705.Chan JN, Hendry G, Biberman A, Bergman K . Architectural exploration of chip-scale photonic interconnection network designs using physical-layer analysis. J Lightw Technol 2010; 28: 1305–1315.Vlasov Y, Green WMJ, Xia FN . High-throughput silicon nanophotonic wavelength-insensitive switch for on-chip optical networks. Nat Photonics 2008; 2: 242–246.Novotny L, van Hulst N . Antennas for light. Nat Photonics 2011; 5: 83–90.Fischer H, Martin OJF . Engineering the optical response of plasmonic nanoantennas. Opt Express 2008; 16: 9144–9154.Dregely D, Taubert R, Dorfmüller J, Vogelgesang R, Kern K et al. 3D optical Yagi-Uda nanoantenna array. Nat Commun 2011; 2: 267.Ni XJ, Emani NK, Kildishev AV, Boltasseva A, Shalaev VM . Broadband light bending with plasmonic nanoantennas. Science 2012; 335: 427.Koenderink AF, Alù A, Polman A . Nanophotonics: shrinking light-based technology. Science 2015; 348: 516–521.Polman A . Plasmonics applied. Science 2008; 322: 868–869.Brongersma ML, Shalaev VM . The case for plasmonics. Science 2010; 328: 440–441.Alù A, Engheta N . Wireless at the nanoscale: optical interconnects using matched nanoantennas. Phys Rev Lett 2010; 104: 213902.Solís DM, Taboada JM, Obelleiro F, Landesa L . Optimization of an optical wireless nanolink using directive nanoantennas. Opt Express 2013; 21: 2369–2377.Dregely D, Lindfors K, Lippitz M, Engheta N, Totzeck M et al. Imaging and steering an optical wireless nanoantenna link. Nat Commun 2014; 5: 4354.Curto AG, Volpe G, Taminiau TH, Kreuzer MP, Quidant R et al. Unidirectional emission of a quantum dot coupled to a nanoantenna. Science 2010; 329: 930–933.Sun J, Timurdogan E, Yaacobi A, Hosseini ES, Watts MR . Large-scale nanophotonic phased array. Nature 2013; 493: 195–199.Van Acoleyen K, Bogarets W, Jágerská J, Le Thomas N, Houdré R et al. Off-chip beam steering with a one-dimensional optical phased array on silicon-on-insulator. Opt Lett 2009; 34: 1477–1479.Van Acoleyen K, Rogier H, Baets R . Two-dimensional optical phased array antenna on silicon-on-insulator. Opt Express 2010; 23: 13655–13660.Rodríguez-Fortuño FJ, Puerto D, Griol A, Bellieres L, Martí J et al. Sorting linearly polarized photons with a single scatterer. Opt Lett 2014; 39: 1394–1397.Krasnok AE, Miroshnichenko AE, Belov PA, Kivshar YS . All-dielectric optical nanoantennas. Opt Express 2012; 20: 20599–20604.Filonov DS, Krasnok AE, Slobozhanyuk AP, Kapitanova PV, Nenasheva EA et al. Experimental verification of the concept of all-dielectric nanoantennas. Appl Phys Lett 2012; 100: 201113.Cárdenas J, Poitras CB, Robinson JT, Preston K, Chen L et al. Low loss etchless silicon photonic waveguides. Opt Express 2009; 17: 4752–4757.Balanis CA . Antenna Theory: Analysis and Design. Wiley: New York; 1982.Kosako T, Kadoya Y, Hofmann HF . Directional control of light by a nano-optical Yagi-Uda antenna. Nat Photonics 2010; 4: 312–315.Subbaraman H, Xu XC, Hosseini A, Zhang XY, Zhang Y et al. Recent advances in silicon-based passive and active optical interconnects. Opt Express 2015; 23: 2487–2511.Della Corte FG, Esposito Montefusco M, Moretti L, Rendina I, Cocorullo G . Temperature dependence analysis of the thermo-optic effect in silicon by single and double oscillator models. J Appl Phys 2000; 88: 7115–7119.Chu T, Yamada H, Ishida S, Arakawa Y . Compact 1 × N thermo-optic switches based on silicon photonic wire waveguides. Opt Express 2005; 13: 10109–10114.Wang WJ, Zhao Y, Zhou HF, Hao YL, Yang JY et al. CMOS-compatible 1 × 3 silicon electrooptic switch with low crosstalk. IEEE Photon Technol Lett 2011; 23: 751–753.Cui KY, Zhao Q, Feng X, Liu F, Huang YD et al Ultra-compact and broadband 1 × 4 thermo-optic switch based on W2 photonic crystal waveguides. Proceedings of 2005 Opto-Electronics and Communications Conference; 28 June–2 July 2015; Shanghai, IEEE: Shanghai 2015.Lee BG, Dupuis N, Pepeljugoski P, Schares L, Budd R et al. Silicon photonic switch fabrics in computer communications systems. J Lightw Technol 2015; 33: 768–777.Song WW, Gatdula R, Abbaslou S, Lu M, Stein A et al. High-density waveguide superlattices with low crosstalk. Nat Commun 2015; 6: 7027.Melati D, Morichetti F, Gentili GG, Melloni A . Optical radiative crosstalk in integrated photonic waveguides. Opt Lett 2014; 39: 3982–3985.Zhang YS, Watts BR, Guo TY, Zhang ZY, Xu CQ et al. Optofluidic device based microflow cytometers for particle/cell detection: a review. Micromachines 2016; 7: 70.Kotz KT, Petrofsky AC, Haghgooie R, Granier R, Toner M et al. Inertial focusing cytometer with integrated optics for particle characterization. Technology (Singap World Sci) 2013; 1: 27–36.Hunt HC, Wilkinson JS . Multimode interference devices for focusing in microfluidic channels. Opt Lett 2011; 36: 3067–3069

    Validation of a Confocal Light Sheet Microscope using Push Broom Translation for Biomedical Applications

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    There exists a need for research of optical methods capable of image cytometry suitable for point-of-care technology. To propose am optical approach with no moving parts for simplification of mechanical components for the further development of the technology to the poin-of-care, a linear sensor with push broom translation method. Push broom translation is a method of moving objects by the sensor for an extended field of view. A polydimethylsiloxane (PDMS) microfluidic chamber with a syringe pump was used to deliver objects by the sensor. The volumetric rate of the pump was correlated to the integration time of the sensor to ensure images were realistically being formed, termed aspect ratio. An electro-chemical microfluidic system was then also investigated, redox-magnetohydrodynamics (R-MHD), to eliminate the mechanical syringe pump which showed deviations in linear speeds at the specimen plane. To image with adequate signal to background ratio within the deep chamber of the R-MHD device, an epitaxial light sheet confocal microscope (e-LSCM) was used to improve axial resolution. The linear sensor, having small pixels, blocked out-of-plane light while eliminating the need for a mechanical aperture which is used for traditional point-scanning confocal microscopy. The particular linear sensor used has binning modes that were used to vary the axial resolution by increasing the sensor aperture. This approach was validated by using a mirror translated in the axial direction and measuring remitted light intensity. The resulting curve estimated the real axial resolution of the microscope, which compared favorably to theoretical values. The R-MHD and the e-LSCM were then synchronized to perform continuous imaging of fluorescent microspheres and cells in suspension. This study combines epitaxial light sheet confocal microscopy and electro-chemical microfluidics as a robust approach which could be used in future point-of-care image cytometry applications

    Portable impedance-sensing device for microparticle characterization

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    À ce jour, quelques biocapteurs ont été proposés pour mesurer rapidement et facilement les caractéristiques et les propriétés des microrganismes individuels membres d'une population hétérogène, mais aucune de ces approches ne s'est avérée être adéquate pour effectuer des mesures directement sur le terrain. Les biocapteurs pour les organismes microscopiques nécessitent généralement une sensibilité ou une spécificité extrême, qui sont difficiles à combiner avec un dispositif général portatif. Cette étude propose un dispositif portatif basé sur la cytométrie de flux d'impédance qui peut détecter et quantifier le diamètre de microbilles de tailles supérieure à 50 µm directement sur le terrain, tout en présentant un faible coût, une taille réduite, une basse consommation de puissance, et une simplicité de conception et d'opération qui maximise le potentiel de l'impression 3D et de la fabrication industrielle de circuits imprimés. Un exemple est offert afin de démontrer les capacités du capteurs pour de larges échantillons, avec un jeu de données contenant 2380 microbilles détectées de tailles entre 50 µm et 90 µm.To this day, a couple of biosensors have been proposed to quickly and easily measure the features and properties of individual microorganisms member of an heterogeneous population, but none of these approaches were adequate candidates to perform measurements directly in the field. Biosensors for micron-scale organisms generally require extreme sensitivity or specificity, which are difficult to combine with a portable general device. This study proposes a portable device based on Impedance Flow-Cytometry that can detect and quantify directly in the fields the size and velocity of microbeads of size bigger than 50 µm, while boasting a low cost, low size, low power, and simplicity of design and operation utilizing the potential of 3D-printing and industrial PCB fabrication. An example is provided for a Big Data application from a sampled dataset containing 2380 successfully detected microbeads of sizes between 50 µm and 90 µm

    Electrochemical sensor system architecture using the CMOS-MEMS technology for cytometry applications

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    This thesis presents the development process of an integrated sensor-system-on-chip for recording the parameters of blood cells. The CMOS based device consists of the two flow-through sensor arrays, stacked one on top of the other. The sensors are able to detect the biological cell in terms of its physical size and the surface charge on a cell’s membrane. The development of the measurement system was divided into several stages these were to design and implement the two sensor arrays complemented with readout circuitry onto a single CMOS chip to create an on-chip membrane with embedded flow-through micro-channels by a CMOS compatible post-processing techniques to encapsulate and hermeti-cally package the device for liquid chemistry experiments, to test and characterise the two sensor arrays together with readout electronics, to develop control and data acquisition software and to detect the biological cells using the complete measurement system. Cy-tometry and haematology fields are closely related to the presented work, hence it is envis-aged that the developed technology enables further integration and miniaturisation of the biomedical instrumentation. The two vertically stacked 4 x 4 flow-through sensor arrays, embedded into an on-chip membrane, were implemented in a single silicon chip device together with a readout circuitry for each of the sensor sets. To develop a CMOS-MEMS device the design and fabrication was carried out using a commercial process design kit (0.35 µm 4-Metal, 2-Poly, CMOS) as well as the foundry service. Thereafter the device was post-processed in-house to develop the on-chip membrane and open the sensing micro-apertures. The two types of sensor were integrated on the silicon dice for multi-parametric characterisation of the analyte. To read the cell membrane charge the ion sensitive field effect transistor (ISFET) was utilised and for cell size (volume) detection an impedance sensor (Coulter counter) was used. Both sensors rely on a flow-through mode of operation, hence the constant flow of the analyte sample could be maintained. The Coulter counter metal electrode was exposed to the solution, while the ISFET floating gate electrode maintained contact with the analyte through a charge sensitive membrane constructed of a dielectric material (silicon dioxide) lining the inside of the micro-pore. The outside size of each of the electrodes was 100 µm x 100 µm and the inside varied from 20 µm x 20 µm to 58 µm x 58 µm. The sense aperture size also varied from 10 µm x 10 µm to 16 µm x 16 µm. The two stacked micro-electrode arrays were layed out on an area of 5002 µm2. The CMOS-MEMS device was fit into a custom printed circuit board (PCB) chip carrier, thereafter insulated and hermetically packaged. Microfluidic ports were attached to the packaged module so that the analyte can be introduced and drained by a flow-through mode of operation. The complete microfluidic system and packaging was assembled and thereafter evaluated for correct operation. Undisturbed flow of the analyte solution is es-sential for the sensor operation. This is related to the fact that the electrochemical response of both sensors depends on the analyte flow through the sense micro-apertures thus any aggregation of the sample within the microfluidic system would cause clogging of the mi-cro-pores. The on-chip electronic circuitry was characterised, and after comparison with the simulated results found to be within an error margin of what enables it for reliable sensor signal readout. The measurement system is automated by software control so that the bias parame-ters can be set precisely, it also helped while error debugging. Analogue signals from the two sensor arrays were acquired, later processed and stored by a data acquisition system. Both control and data capture systems are implemented in a high level programming lan-guage. Furthermore both are integrated and operated in a one window based graphical user interface (GUI). A fully functional measurement system was used as a flow-through cytometer for living cells detection. The measurements results showed that the system is capable of single cell detection and on-the-fly data display

    Test analysis & fault simulation of microfluidic systems

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    This work presents a design, simulation and test methodology for microfluidic systems, with particular focus on simulation for test. A Microfluidic Fault Simulator (MFS) has been created based around COMSOL which allows a fault-free system model to undergo fault injection and provide test measurements. A post MFS test analysis procedure is also described.A range of fault-free system simulations have been cross-validated to experimental work to gauge the accuracy of the fundamental simulation approach prior to further investigation and development of the simulation and test procedure.A generic mechanism, termed a fault block, has been developed to provide fault injection and a method of describing a low abstraction behavioural fault model within the system. This technique has allowed the creation of a fault library containing a range of different microfluidic fault conditions. Each of the fault models has been cross-validated to experimental conditions or published results to determine their accuracy.Two test methods, namely, impedance spectroscopy and Levich electro-chemical sensors have been investigated as general methods of microfluidic test, each of which has been shown to be sensitive to a multitude of fault. Each method has successfully been implemented within the simulation environment and each cross-validated by first-hand experimentation or published work.A test analysis procedure based around the Neyman-Pearson criterion has been developed to allow a probabilistic metric for each test applied for a given fault condition, providing a quantitive assessment of each test. These metrics are used to analyse the sensitivity of each test method, useful when determining which tests to employ in the final system. Furthermore, these probabilistic metrics may be combined to provide a fault coverage metric for the complete system.The complete MFS method has been applied to two system cases studies; a hydrodynamic “Y” channel and a flow cytometry system for prognosing head and neck cancer.Decision trees are trained based on the test measurement data and fault conditions as a means of classifying the systems fault condition state. The classification rules created by the decision trees may be displayed graphically or as a set of rules which can be loaded into test instrumentation. During the course of this research a high voltage power supply instrument has been developed to aid electro-osmotic experimentation and an impedance spectrometer to provide embedded test

    Micro/nano devices for blood analysis

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    [Excerpt] The development of microdevices for blood analysis is an interdisciplinary subject that demandsan integration of several research fields such as biotechnology, medicine, chemistry, informatics, optics,electronics, mechanics, and micro/nanotechnologies.Over the last few decades, there has been a notably fast development in the miniaturization ofmechanical microdevices, later known as microelectromechanical systems (MEMS), which combineelectrical and mechanical components at a microscale level. The integration of microflow and opticalcomponents in MEMS microdevices, as well as the development of micropumps and microvalves,have promoted the interest of several research fields dealing with fluid flow and transport phenomenahappening at microscale devices. [...

    Micro- and Nanofluidics for Bionanoparticle Analysis

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    Bionanoparticles such as microorganisms and exosomes are recoganized as important targets for clinical applications, food safety, and environmental monitoring. Other nanoscale biological particles, includeing liposomes, micelles, and functionalized polymeric particles are widely used in nanomedicines. The recent deveopment of microfluidic and nanofluidic technologies has enabled the separation and anslysis of these species in a lab-on-a-chip platform, while there are still many challenges to address before these analytical tools can be adopted in practice. For example, the complex matrices within which these species reside in create a high background for their detection. Their small dimension and often low concentration demand creative strategies to amplify the sensing signal and enhance the detection speed. This Special Issue aims to recruit recent discoveries and developments of micro- and nanofluidic strategies for the processing and analysis of biological nanoparticles. The collection of papers will hopefully bring out more innovative ideas and fundamental insights to overcome the hurdles faced in the separation and detection of bionanoparticles
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